June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Targeting the STRA6/RBP4 Binding interaction to Treat Macular Degeneration
Author Affiliations & Notes
  • Krysten Farjo
    Physiology, Univ of Oklahoma Hlth Sciences, Oklahoma City, OK
  • Gennadiy Moiseyev
    Physiology, Univ of Oklahoma Hlth Sciences, Oklahoma City, OK
  • Jian-Xing Ma
    Physiology, Univ of Oklahoma Hlth Sciences, Oklahoma City, OK
  • Footnotes
    Commercial Relationships Krysten Farjo, None; Gennadiy Moiseyev, Charlesson LLC (E); Jian-Xing Ma, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1702. doi:
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    • Get Citation

      Krysten Farjo, Gennadiy Moiseyev, Jian-Xing Ma; Targeting the STRA6/RBP4 Binding interaction to Treat Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1702.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Macular degeneration is initiated and perpetuated by the accumulation of toxic Vitamin A derivatives in the retinal pigment epithelium (RPE). Pharmacological inhibition of Vitamin A delivery or metabolism in the RPE can significantly slow and reduce vision loss in animal models of macular degeneration. Serum retinol binding protein (RBP4) transports Vitamin A, and delivers Vitamin A to RPE through binding to its receptor, STRA6. We sought to develop and characterize novel inhibitory peptides that target the STRA6/RBP4 interaction to reduce Vitamin A delivery to RPE.

Methods: We synthesized candidate inhibitory peptides based on the protein domains of STRA6 that are implicated in binding to RBP4 (including C43, C194-Q196, Y335-G341, and R461-N462). HEK-293 cells were used to generate a STRA6-stable cell line, which served as the basis for the development of a high throughput STRA6/RBP4 competition binding assay in which alkaline phosphatase-tagged RBP4 (AP-RBP4) is incubated with STRA6-stable cells alone or in combination with increasing concentrations of candidate inhibitory peptides. Quantification of AP activity is proportional to the amount of AP-RBP4 bound to STRA6-stable cells. In addition, we have established a cellular Vitamin A uptake assay to evaluate the efficacy of inhibitory peptides to reduce STRA6-mediated uptake of Vitamin A in STRA6-stable cells.

Results: We have identified four inhibitory peptides that significantly reduce the STRA6/RBP4 binding interaction and/or inhibit STRA6-mediated Vitamin A uptake.

Conclusions: Peptides derived from the STRA6 protein domains implicated in binding to RBP4 have inhibitory activity to significantly reduce STRA6/RBP4 binding and STRA6-mediated Vitamin A uptake in cell culture. Ongoing studies are evaluating the ability of these peptides to inhibit Vitamin A uptake and visual cycle activity in mouse eyecups. These inhibitory peptides could serve as the basis for the development of a novel therapeutic to treat macular degeneration.

Keywords: 705 retinoids/retinoid binding proteins • 412 age-related macular degeneration • 701 retinal pigment epithelium  
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